Viral molecular mechanisms

In this project, we are investigating a process that viruses use to initiate infection — the molecular mechanisms by which they deposit their genetic material into cells.

When a virus fuses its coating membrane (known as an envelope) with a cell membrane, a fusion pore is created. This pore connects the interior of the virus to that of the cell. The viral genome passes through this pore and enters the cell’s cytosol. Proteins within the viral envelope, called fusion proteins, drive fusion, but many cellular factors regulate the process.

Our goal is to discover and identify the mechanisms and cellular controls for viral fusion, and to formulate general principles that can be applied to prevent infection. Over the years, we have studied fusion induced by the proteins of HIV, influenza, leukemia viruses and Ebola, and we have identified common mechanisms among them as well as specifics that apply to only a particular virus.

We have also identified ways that cellular proteins and physical properties of membranes regulate fusion, for example, via electrical voltages across them. We are currently mostly focused on how a class of cellular membrane proteins (SERINCs) control enlargement of the HIV fusion pore and how cellular factors and proteins directly regulate the activity of the fusion protein of Ebola virus.

Cholesterol regulation

Our second project is directed toward discovering how the chemical potential of cholesterol in cellular plasma membranes regulates cellular pathologies. The concentration of cholesterol is easily and routinely measured. But it is the chemical activity, and not the concentration, of a substance, including cholesterol, that has biological relevance. Chemical activity is the “effective” concentration and is rigorously quantified by chemical potential.

A major obstacle to understanding has been the lack of an accurate procedure to measure cholesterol’s chemical potential. We have recently developed such a procedure. Implementing this procedure, we have found that the chemical potential of cholesterol within plasma membranes significantly increases when cells become inflamed. This chemical potential also increases when cancer cells become metastatic.

Further, we have developed a means to control and fix this chemical potential and, in doing so, we found that preventing the chemical potential from increasing severely reduces metastasis and cellular inflammation. It, thus, appears that the chemical potential of membrane cholesterol is a key control in both inflammation and metastasis, and that interventions that regulate this chemical potential may be critical in controlling important pathologies.